An Indiana University biologist has been awarded over $2.3 million from the National Institutes of Health to genetically modify variants of the human pathogen chlamydia in hopes of finding a vaccine for the most commonly reported bacterial infectious disease in the United States.
David E. Nelson, an assistant professor in the IU Bloomington College of Arts and Sciences' Department of Biology, and researchers in his laboratory plan to genetically backtrack the trail of a consummate bacterial parasite -- Chlamydia trachomatis -- by mutating and characterizing the functions of targeted genes of the pathogen. According to the U.S. Centers for Disease Control and Prevention, more than 1.3 million Americans were infected with chlamydia in 2010, the largest number of cases ever reported to CDC for any condition.
Nelson's team will use the NIH funding over the next five years to try to understand how the bacterial pathogen circumvents host immune systems and targets preferred tissues, resulting in sexually transmitted infections and blinding trachoma in hundreds of millions of people, as well as billions of dollars in annual health care costs worldwide.
"Understanding the pathogenesis of a disease, how it originates and develops, is by necessity a cross-disciplinary exercise that in this case brings together research in model organisms, microbiology and genomics in an attempt to better understand the virulence of a very nasty pathogen," Nelson said. "A major reason for gaps in our knowledge has been that bacteria in this genus, of which multiple variants are human pathogens, could not be genetically manipulated."
What limits genetic manipulation of chlamydia, and what makes it particularly nasty, he said, is that the bacteria live protected inside human and animal cells, which prevents the standard method of gene manipulation -- inserting foreign DNA into bacteria -- from being used.
But by taking an approach previously used extensively in plant genetics called targeting-induced local lesions in genomes, newly developed genetic tools now make it possible for researchers to better explore genes they believe help determine the types of tissues and hosts that different chlamydia species infect. One of the first places Nelson's team is looking is in a genomic region called the plasticity zone, where much of the genetic variation among the disease-causing strains of chlamydia appears to reside.
"With these new tools we can use a reverse genetic approach to inactivate plasticity zone (PZ) genes and then test to see if the mutants that we've created have certain sensitivities or have alterations in pathogenicity," Nelson said. "One of our suspicions is that PZ genes counteract host cell proteins that mediate immunity."
By isolating plasticity zone mutants, the lab hopes to determine whether PZ genes dictate certain niche attributes. By employing genetic screens, they may be able to identify the genes chlamydia species use to target certain tissues and circumvent immunity. The group will also use forward genetic screens, lateral gene transfer and genome sequencing, among other tools, to try to understand which chlamydia genes work to evade host immune responses and to identify the genetic blueprint in animals and humans that could offer insight into why host defenses are sensitive to chlamydia.
"In the long term we hope our work provides clues toward designing a vaccine and developing strong models of human chlamydial disease," Nelson said. "But most immediately we're looking to identify and characterize the factors that allow this pathogen to grow, how it interacts with other bacteria and how it avoids host immune systems so well."
Women, especially young and minority women, are hardest hit by chlamydia, and the CDC recommends annual chlamydia screening for young women under the age of 26. Earlier this month, the CDC said the actual rate of new infections in the U.S. during 2010 may have been nearly 2.8 million because the infection often has no symptoms.